FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the memory deficits in rats through a novel mechanism of action.
FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the memory deficits in rats through a novel mechanism of action.
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FK960 N-(4-乙酰基-1-哌嗪基)-对氟苯甲酰胺一水合物通过一种新的作用机制改善大鼠的记忆缺陷。
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
I. Yamaguchi
中科院分区：
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作者：
M. Yamazaki;N. Matsuoka;N. Maeda;Y. Ohkubo;I. Yamaguchi
通过被动回避 (PA)、莫里斯水迷宫 (WM) 和八臂径向迷宫任务，我们评估了 FK960 [N-(4-乙酰基-1-哌嗪基)-对氟苯甲酰胺一水合物] 的记忆增强作用，该化合物是我们基于阴茎勃起是中枢胆碱能激活的有效预测因子这一假设，通过合理的药物筛选发现的化合物。老年（24 至 26 个月大）大鼠以及大细胞基底核损伤的大鼠在任务中的记忆表现受损。东莨菪碱 (1 mg/kg i.p.) 治疗引起 PA 和 WM 的记忆障碍；半胱胺（200 mg/kg s.c.）治疗可引起 PA 记忆损伤，但不会引起 WM 记忆损伤，而穹窿伞损伤以相反的方式影响大鼠。 FK960（0.1-10 mg/kg i.p.）改善了除半胱胺或穹窿伞损伤引起的记忆障碍外的所有记忆障碍，并且剂量反应曲线呈钟形，最大反应在1至3.2 mg/kg时。 FK960 对东莨菪碱引起的 PA 和/或 WM 记忆损伤的作用可被半胱胺（200 mg/kg 皮下注射）、dl-对氯苯丙氨酸甲酯盐酸盐（150 mg/kg 腹膜内注射 3 天）或中缝损伤消除，但不能通过新生儿 6-羟基多巴胺（35 微克/头）治疗消除。神经化学分析显示，半胱胺和中缝损伤分别降低了大脑生长抑素和血清素的含量。 FK960（0.32-320mg/kg，口服）治疗剂量依赖性地增加了所检查的大脑区域中的血清素和5-羟基吲哚乙酸水平，并且在较小剂量下显着增加了海马生长抑素的含量。从这些结果中，我们得出结论，FK960 通过激活生长抑素能-血清素能联系来改善认知功能障碍。
With passive avoidance (PA), Morris water maze (WM) and eight-arm radial maze tasks, we evaluated the memory-enhancing action of FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a compound which we have found through rational drug screening based on our hypothesis that penile erection is a valid predictor of central cholinergic activation. Memory performance in the tasks was impaired in aged (24- to 26-months-old) rats as well as in rats with nucleus basalis magnocellularis lesions. Scopolamine (1 mg/kg i.p.) treatment induced memory impairment in PA and WM; treatment with cysteamine (200 mg/kg s.c.) induced memory impairment in PA but not in WM, whereas fimbria fornix lesioning affected the rats in the opposite manner. FK960 (0.1-10 mg/kg i.p.) ameliorated all the memory impairments except those induced by cysteamine or fimbria fornix lesion, and the dose-response curves were bell shaped with maximal response at 1 to 3.2 mg/kg. The effects of FK960 on the scopolamine-induced memory impairment in the PA and/or WM were abolished by cysteamine (200 mg/kg s.c.), dl-p-chlorophenylalanine methyl ester hydrochloride (150 mg/kg i.p. for 3 days) or raphe lesioning, but not by neonatal 6-hydroxydopamine (35 micrograms/head) treatment. Neurochemical analysis revealed that cysteamine and raphe lesions reduced brain somatostatin and serotonin contents, respectively. The treatment with FK960 (0.32-320 mg/kg p.o.) dose-dependently increased both serotonin and 5-hydroxyindoleacetic acid levels in the brain areas examined and significantly increased hippocampal somatostatin contents at the smaller doses. From these results, we conclude that FK960 ameliorates cognitive dysfunction through an activation of the somatostatinergic-serotonergic link.